Development of a Safe and High-Throughput Continuous Manufacturing Approach to 4-(2-Hydroxyethyl)thiomorpholine 1,1-Dioxide

Continuous processing enabled the highly energetic double conjugate addition of ethanolamine to divinylsulfone to prepare 2 kg of 4-(2-hydroxyethyl)thiomorpholine 1,1-dioxide, as an intermediate in the synthesis of HIV Maturation Inhibitor BMS-955176. In situ IR was employed to monitor the steady state of the transformation for increased robustness via appearance of the thiomorpholine dioxide moiety and disappearance of the divinylsulfone. Surprisingly, a series of oligomers formed as intermediates, which converted to product with extended aging or heating, consistent with computational predictions. By running this process in flow, the highly exothermic reaction could be safely executed in an equal volume of water as the only solvent, despite an adiabatic temperature rise of 142 °C, leading to a streamlined and efficient process.